The present invention relates to compounds and pharmaceutical compositions that are selective antagonists of A2B adenosine receptors (ARs). These compounds and compositions are useful as pharmaceutical agents.
The alkylxanthine theophylline (compound 1, FIG. 1), a weak non-selective adenosine antagonist (See Linden, J., et al., in Cardiovascular Biology of Purines, eds. G. Burnstock, et al., 1998, pp 1-20.) is useful therapeutically for the treatment of asthma. However, its use is associated with unpleasant side effects, such as insomnia and diuresis. (See Vassallo, R. et al., Mayo. Clin. Proc. 1998, 73, 346-354.) In recent years, the use of theophylline as a bronchodilator, for relief of asthma, has been supplanted by drugs of other classes, i.e., selective xcex22-adrenergic agonists, corticosteroids, and recently leukotriene antagonists. (See Drazen, J. M., et al., New Eng. J. Med. 1999, 340, 197-206.) These compounds also have limitations, thus, the development of a theophylline-like drug with reduced side effects is still desirable.
It has been recognized that theophylline and its closely related analogue caffeine block endogenous adenosine acting as a local modulator of adenosine receptors in the brain and other organs at therapeutically useful doses. Adenosine activates four subtypes of G protein-coupled adenosine receptors (ARs), A1/A2A/A2B/A3. (See Fredholm, B. B., et al., Pharmacol. Rev. 1999, 51, 83-133.) In comparison to the other known actions of theophylline, e.g., inhibition of phosphodiesterases, theophylline is more potent in antagonism of adenosine receptors. Enprofylline, (compound 3, FIG. 1) a compound that is used to treat asthma, is another example of a xanthine that has been reported to block A2B adenosine receptors. However, this compound only weakly blocks A1, A2A and A3 adenosine receptors.
It has been reported that therapeutic concentrations of theophylline or enprofylline block human A2B receptors, and it has been proposed that antagonists selective for this subtype may have potential use as antiasthmatic agents. (See Feoktistov, I., et al., Pharmacol. Rev. 1997, 49, 381-402; and Robeva, A. S., et al., Drug Dev. Res. 1996, 39, 243-252. Enprofylline has a reported Ki value of 7 xcexcM and is somewhat selective in binding to human A2B ARs. (See Robeva, A. S., et al., Drug Dev. Res. 1996, 39, 243-252 and Linden, J., et al., Mol. Pharmacol. 1999, 56, 705-713.) A2B ARs are expressed in some mast cells, such as the BR line of canine mastocytoma cells, which appear to be responsible for triggering acute Ca2+ mobilization and degranulation. (See Auchampach, J. A., et al., Mol. Pharmacol. 1997. 52, 846-860 and Forsyth, P., et al., Inflamm. Res. 1999, 48, 301-307.) A2B ARs also trigger Ca2+ mobilization, and participate in a delayed IL8 release from human HMC-1 mast cells. Other functions associated with the A2B AR are the control of cell growth and gene expression, (See Neary, J., et al., Trends Neurosci. 1996, 19, 13-18.) endothelial-dependent vasodilation (See Martin, P. L., et al., J. Pharmacol. Exp. Ther. 1993, 265, 248-253.), and fluid secretion from intestinal epithelia. (See Strohmeier, G. R., et al., J. Biol. Chem. 1995, 270, 2387-2394.) Adenosine acting through A2B ARs has also been reported to stimulate chloride permeability in cells expressing the cystic fibrosis transport regulator. (See Clancy, J. P., et al., Am. J. Physiol. 1999, 276, C361-C369.)
Although adenosine receptor subtype-selective probes are available for the A1, A2A, and A3 ARs, only few weakly selective antagonists and no selective agonists are known for the A2B receptor. Therefore, a continuing need exists for compounds that are selective A2B receptor antagonists.
The present invention provides compounds that act as antagonists of A2B adenosine receptors. Accordingly, the present invention provides a compound of formula I: 
wherein R, and R1 are independently hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-8)alkoxy, (C3-C8)cycloalkyl, (C4-C16)cycloalkylalkyl, hetero-cycle, (C6-C10)aryl, (C7-C18)aralkyl or heteroaryl; 
X is (C1-C8)alkylene, (C2-C8)alkenylene, (C2-C8)alkynylene, wherein one of the carbon atoms in the alkylene, alkenylene or alkynylene groups can be replaced with group having the formula xe2x80x94Oxe2x80x94, xe2x80x94N(R4)C(O)xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94N(R5)(R6)xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94 or xe2x80x94SO2xe2x80x94, wherein
R2 is hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C8)alkoxy, (C3-C8)cycloalkyl, (C3-C8)heterocycle, (C6-C10)aryl, (C6-C10)heteroaryl, (C4-C16)cycloalkylalkyl or (C7-C18)aralkyl, optionally substituted with one or more substituents selected from the group consisting of xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2, xe2x80x94NHR7, xe2x80x94CN, xe2x80x94CO2H, and xe2x80x94SO3H, wherein
R4, R5, R6 and R7 are independently hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C3-C8)cycloalkyl, (C6-C10)aryl, (C7-C18)aralkyl or halo(C1-C6)alkyl,
wherein R8 is hydrogen, (C3-C8)cycloalkyl, (C4-C16)cycloalkylalkyl, (C7-C18)aralkyl, heterocycle or heteroaryl, each optionally substituted with one or more substituents, wherein the substituents independently are oxo, (C1-C8)alkyl, halo(C1-C6)alkyl, (C2-C8)alkenyl, (C6-C10)aryl, (C7-C18)aralkyl, heteroaryl, halo, xe2x80x94OR15, xe2x80x94CN, xe2x80x94NO2, xe2x80x94CO2R15, xe2x80x94OC(O)R16, xe2x80x94C(O)R16, xe2x80x94NR13R14, xe2x80x94N(R23)C(O)R24, xe2x80x94C(O)NR17R18, xe2x80x94SR19, xe2x80x94SO2R20 or xe2x80x94SO3H; or
R8 is (C1-C8)alkyl, substituted with one or more substituents independently selected from the group consisting of oxo, (C2-C8)alkenyl, (C6-C10)aryl, (C7-C18)aralkyl, heteroaryl, halo xe2x80x94OR15, xe2x80x94CN, xe2x80x94NO2, xe2x80x94CO2R15, xe2x80x94OC(O)R16, xe2x80x94C(O)R16, xe2x80x94NR13R14, xe2x80x94N(R23)C(O)R24, xe2x80x94C(O)NR17R18, xe2x80x94SR19, xe2x80x94SO2R20 and xe2x80x94SO3H; or
R8 is (C6-C10)aryl, substituted with one or more substituents independently selected from the group consisting of (C1-C8)alkyl, halo(C1-C6)alkyl, (C2-C8)alkenyl, (C7-C18)aralkyl, heteroaryl, xe2x80x94OR15, xe2x80x94CN, xe2x80x94NO2, xe2x80x94CO2R15, xe2x80x94OC(O)R16, xe2x80x94C(O)R16, xe2x80x94NR13R14, xe2x80x94N(R23)C(O)R24, xe2x80x94C(O)NR17R18, xe2x80x94SR19, xe2x80x94SO2R20 and xe2x80x94SO3H; and
wherein R9 is xe2x80x94NR10R11, or R9 is (C3-C8)cycloalkyl, (C4-C16)cycloalkylalkyl, (C7-C18)aralkyl, heterocycle or heteroaryl, each optionally substituted with one or more substituents, wherein the substituents independently are oxo, (C1-C8)alkyl, halo(C1-C6)alkyl, (C2-C8)alkenyl, (C6-C10)aryl, (C7-C18)aralkyl, heteroaryl, xe2x80x94OR15, halo, xe2x80x94CN, xe2x80x94NO2, xe2x80x94CO2R15, xe2x80x94OC(O)R16, xe2x80x94C(O)R16, xe2x80x94NR13R14, xe2x80x94N(R23)C(O)R24, xe2x80x94C(O)NR17R18, xe2x80x94SR19, xe2x80x94SO2R20 or xe2x80x94SO3H; or
R9 is (C1-8)alkyl, substituted with one or more substituents independently selected from the group consisting of oxo, (C2-C8)alkenyl, (C6-C10)aryl, (C7-C18)aralkyl, heteroaryl, xe2x80x94OR15, halo, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OC(O)R16, xe2x80x94C(O)R16, xe2x80x94NR13R14, xe2x80x94N(R23)C(O)R24, xe2x80x94C(O)NR17R18, xe2x80x94SR19, xe2x80x94SO2R20 and xe2x80x94SO3H;
R9 is (C6-C10)aryl, substituted with one or more substituents independently selected from the group consisting of (C1-C8)alkyl, halo(C1-C6)alkyl, (C2-C8)alkenyl, (C7-C18)aralkyl, heteroaryl, xe2x80x94OR15, xe2x80x94CN, xe2x80x94NO2, xe2x80x94CO2R15, xe2x80x94OC(O)R16, xe2x80x94C(O)R16, xe2x80x94NR13R14, xe2x80x94N(R23)C(O)R24, xe2x80x94C(O)NR17R18, xe2x80x94SR19, xe2x80x94SO2R20 and xe2x80x94SO3H, and
wherein R10 and R11 are independently hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C3-C8)cycloalkyl, (C6-C10)aryl, (C7-C18)aralkyl, heterocycle, heteroaryl, xe2x80x94C(O)(CH2)nCO2R12, xe2x80x94C(O)CR21xe2x95x90CR22(CH2)mCO2R12, xe2x80x94C(O)R12, xe2x80x94C(O)(C3-C8)cycloalkyl or xe2x80x94C(O)(C3-C8)cycloalkenyl, each optionally substituted with one or more substituents, wherein the substituents independently are oxo, (C1-C8)alkyl, halo(C1-C6)alkyl, (C2-C8)alkenyl, (C6-C10)aryl, (C7-C18)aralkyl, heteroaryl, xe2x80x94OR15, halo, xe2x80x94CN, xe2x80x94NO2, xe2x80x94CO2R15, xe2x80x94OC(O)R16, xe2x80x94C(O)R16, xe2x80x94NR13R14, xe2x80x94N(R23)C(O)R24, xe2x80x94C(O)NR17R18, xe2x80x94SR19, xe2x80x94SO2R20 or xe2x80x94SO3H; or the R10 and R11 groups and the nitrogen atom can be taken together to form a heterocyclic ring or a heteroaryl ring, each ring optionally substituted with one or more substituents, wherein the substituents independently are oxo, (C1-C8)alkyl, halo(C1-C6)alkyl, (C2-C8)alkenyl, (C6-C10)aryl, (C7-C18)aralkyl, heteroaryl, xe2x80x94OR15, halo, xe2x80x94CN, xe2x80x94NO2, CO2R15, xe2x80x94OC(O)R16, xe2x80x94C(O)R16, xe2x80x94NR13R14, xe2x80x94N(R23)C(O)R24, xe2x80x94C(O)NR17R18, xe2x80x94SR19, xe2x80x94SO2R20 or xe2x80x94SO3H; wherein n is 1 to 6, and m is 0 to 4;
R12 is hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (C4-C16)cycloalkylalkyl, (C6-C10)aryl, (C7-C18)aralkyl, hetero-cycle, or heteroaryl,
wherein the R12 group is optionally substituted with one or more substituents independently selected from the group consisting of oxo, (C1-C8)alkyl, halo(C1-C6)-alkyl, (C2-C8)alkenyl, (C6-C10)aryl, (C7-C18)aralkyl, heteroaryl, xe2x80x94OR15, halo, xe2x80x94CN, xe2x80x94NO2, xe2x80x94CO2R15, OC(O)R16, xe2x80x94C(O)R16, xe2x80x94NR13R14, xe2x80x94N(R23)C(O)R24, xe2x80x94C(O)NR17R18, xe2x80x94SR19, xe2x80x94SO2R20 or xe2x80x94SO3H.
The R13, R14, R15, R16, R17, R18, R19, R20, R23 and R24 groups are independently hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C3-C8)cycloalkyl, (C6-C10)aryl, (C7-C18)aralkyl or halo(C1-C6)alkyl; and the R21 and R22 groups are independently hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C3-C8)cycloalkyl, (C6-C10)aryl, (C7-C18)aralkyl.
The invention also provides pharmaceutically acceptable salts of a compound of formula I. The invention also provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.
Additionally, the invention provides a therapeutic method for preventing or treating a pathological condition or symptom in a mammal, such as a human, wherein the activity, i.e., over-activity, of adenosine A2B receptors is implicated in one or more symptoms of the pathology and antagonism (i.e., blocking) of their activity is desired to ameliorate said symptoms. Such diseases or conditions include, but are not limited to, asthma, diarrheal diseases, insulin resistance, diabetes, prevention of mast cell degranulation associated with ischemia/reperfusion injuries, inhibition of angiogenesis in neoplastic tissues, and inhibition of angiogenesis in diabetic retinopathy or hyperbaric oxygen-induced retinopathy. The invention also includes a method for treating asthma, diarrheal diseases, insulin resistance, diabetes, inhibition of angiogenesis in neoplastic tissues, and inhibition of angiogenesis in diabetic retinopathy or hyperbaric oxygen-induced retinopathy in a mammal, (e.g., a human) comprising administering to the mammal in need of such therapy, an effective amount of at least one compound of formula I or pharmaceutically acceptable salt(s) thereof.
The invention provides a compound of formula I for use in medical therapy preferably for use in treating diseases or conditions associated with deleterious A2B receptor activation or activity, including asthma, diarrheal diseases, insulin resistance, diabetes, ischemic/reperfusion injury, inhibition of angiogenesis in neoplastic tissues, and inhibition of angiogenesis in diabetic retinopathy or hyperbaric oxygen-induced retinopathy, as well as the use of a compound of formula I for the manufacture of a medicament for the treatment of a pathological condition or symptom in a mammal, such as a human, which is associated with deleterious A2B receptor activation or activity, including the above-referenced diseases or pathologies.
The invention also includes a method comprising contacting a compound of formula I, optionally having a radioactive isotope (radionuclide), such as, for example, tritium, radioactive iodine (for example, 125I for binding assays or 123I for Spect Imaging) and the like, with target A2B adenosine receptor sites comprising said receptors, in vivo or in vitro, so as to bind said receptors. Cell membranes comprising bound A2B adenosine receptor sites can be used to measure the selectivity of test compounds for adenosine receptor subtypes or can be used as a tool to identify potential therapeutic agents for the treatment of diseases or conditions associated with A2B-receptor mediation, by contacting said agents with said radioligands and receptors, and measuring the extent of displacement of the radioligand and/or binding of the agent.